Aggressive Retinal Astrocytomas in 4 Patients With Tuberous Sclerosis Complex

Retinal astrocytic hamartoma is the best-known ocular manifestation of tuberous sclerosis complex (TSC).^1,2 It is generally a sessile or slightly elevated lesion in the nerve fiber layer of the retina, but it can have several clinical variations. It can be unilateral, bilateral, solitary, multifocal, transparent, opaque, noncalcified, or calcified.^1,2 Retinal astrocytic hamartoma in association with TSC generally is considered to be a relatively stationary lesion that has little potential for aggressive behavior.^1-5 In rare instances, however, a retinal astrocytic hamartoma can show progressive growth and cause severe local complications. We report the clinical course and histopathologic findings in 4 patients with TSC, each of whom developed progressive growth of a juxtapapillary astrocytic hamartoma that caused secondary retinal detachment and neovascular glaucoma, necessitating enucleation of the affected eye.

The clinical records and histopathologic findings were reviewed and summarized on 4 patients with TSC who underwent enucleation of 1 eye because of tumor growth and neovascular glaucoma. Clinical findings evaluated included patient age at enucleation; patient sex; tumor dimensions; and frequency of retinal exudation, retinal detachment, neovascular glaucoma, and extraocular extension. Assessment of pathology findings included review of grossly sectioned eyes, histopathologic sections, and immunohistochemical preparations. The literature on aggressive retinal astrocytic neoplasms that came to enucleation was reviewed, and a comparison was made between those associated with TSC and those unassociated with TSC.

In the computerized files of the Ocular Oncology Service at Wills Eye Hospital, we identified 4 cases of aggressive astrocytic retinal tumors associated with TSC that required enucleation. The TSC in each patient was characterized by hypopigmented cutaneous macules, facial angiofibromas, and subependymal or cortical lesions typical of TSC seen with computed tomography or magnetic resonance imaging. One patient had renal cysts and none had cardiac, lung, or other lesions of TSC.

Concerning ocular manifestations, each patient had a similar clinical course, characterized by progressive enlargement of a previously recognized yellow retinal juxtapapillary mass (Figure 1) that ultimately caused a blind painful eye and necessitated enucleation. In addition, 3 of the 4 patients had multiple retinal astrocytic tumors in both eyes, and only 1 patient had a solitary retinal tumor.

The pertinent clinical information on our 4 cases is summarized in Table 1. There were 2 boys and 2 girls. Each tumor was surrounded by yellow intraretinal exudation that was documented to slowly progress to a total exudative retinal detachment and neovascular glaucoma. This progressive exudation and retinal detachment appeared to be directly related to gradual enlargement of the tumor. The intervals from the initial diagnosis of retinal tumor to enucleation ranged from 6 months to 13 years. In the latter patient with the 13-year interval, enucleation had been advised at age 7 years, but the parents had refused and only consented to enucleation when the tumor caused perforation of the globe 6 years later. Based on clinical estimation and ultrasonography, the tumor sizes at the time of enucleation ranged from 12 × 8 × 9 mm to 20 × 20 × 25 mm, with the latter (case 4) being the tumor that filled the entire globe and perforated the cornea. Seven years earlier, that tumor measured 8 × 8 × 4 mm, attesting to the relentless slow growth that characterized all of the tumors.

It is of interest that the smaller, more peripheral astrocytomas in the ipsilateral and contralateral eyes of 3 patients did not exhibit growth during the course of follow-up, ranging from 3 to 12 years. In every case, only 1 larger tumor near the optic disc showed progressive growth and retinal detachment, whereas all other tumors remained stationary.

Two of our patients (cases 2 and 3) had surgical attempts elsewhere to control the growing tumor and the retinal detachment by laser, vitrectomy, and retinal reattachment. In each case, the attempts failed and there was slow relentless growth of the tumor.

The macroscopic appearance of the sectioned enucleated eyes is illustrated in Figure 2, Figure 3, Figure 4, and Figure 5. In cases 1 through 3, yellow-white tumors arose from the posterior retina in the region of the optic disk. These tumors measured 7, 10, and 14 mm in the largest diameter and were associated with total secondary retinal detachments. Two were predominantly exophytic, and the third had a combined exophytic-endophytic growth pattern. In case 4, the neoplasm filled the entire globe and perforated the sclera.

Pertinent histopathologic features are summarized in Table 2. All 4 eyes had florid iris neovascularization and secondary angle closure (Figure 6), and all had total nonrhegmatogenous exudative retinal detachments. The retina in case 4 was largely destroyed. All 4 neoplasms contained extensive areas of necrosis, comprising 50% to 95% of the tumor (Figure 7). Each of the retinal neoplasms was composed of 2 types of cells that were present in varying proportions. One group of cells had copious quantities of pale eosinophilic cytoplasm and resembled those found in subependymal giant cell astrocytoma of the brain in TSC (Figure 8). These giant cells typically were large and round or oval in profile, and the periphery of their cytoplasm occasionally was vacuolated. Many of the giant cells had large round or oval nuclei with prominent nucleoli. The cells in the second group were more elongated and fusiform in shape and had more intensely eosinophilic cytoplasm and smaller, darker nuclei (Figure 9). In several cases, the retina and the parenchyma of the optic nerve contained large numbers of these plump spindle cells. The large, aggressive neoplasm in case 4 had invaded the choroid and optic nerve; it had moderate degree of nuclear pleomorphism and atypia and occasional mitotic figures. Glial cells with abundant cytoplasm were found in the retrolaminar part of the atrophic optic nerve in all cases. All of the astrocytic tumors contained foci of basophilic, multilaminated calcospherites (Figure 10), and 2 eyes contained metaplastic bone, hamartomas of the iris, and ciliary epithelia. The latter finding has been reported previously.⁶

The results of special immunohistochemical studies are summarized in Table 3. All tumors coexpressed neuronal marker neuron-specific enolase (NSE) and glial marker glial fibrillary acidic protein (GFAP). In general, the giant cells were immunoreactive for NSE but were negative or only minimally reactive for GFAP (Figure 11). In contrast, the spindle cells expressed both NSE and GFAP (Figure 12). The tumor cells also were strongly immunoreactive for S100 protein and vimentin. Melanoma marker HMB-45 was uniformly negative.

Reported cases of aggressive retinal astrocytomas without clinical evidence of TSC are summarized in Table 4. We were able to identify 12 reported cases that we believe are acceptable based on a review of the clinical descriptions and the illustrations.^7-17 Reported cases of aggressive retinal astrocytomas in patients with TSC, including our 4 cases, are summarized in Table 5. Our literature search revealed 5 previously reported acceptable cases of aggressive retinal astrocytic hamartomas that were clearly associated with TSC,^18-22 1 of which is included in our series of 4 cases.²²

A comparison of Table 4 and Table 5 suggests that there are many similarities between aggressive retinal astrocytomas unassociated with overt manifestations of TSC and those associated with TSC. However, those unassociated with TSC tended to require enucleation at an older age, and choroidal melanoma was often a diagnostic consideration prior to enucleation. All were solitary lesions that occurred in patients who had no other fundus tumors or other abnormalities. There appeared to be a greater component of spindle cells in tumors unassociated with TSC, but this was difficult to assess accurately in our literature review. Otherwise, there were no important clinical or histopathologic differences between the 2 groups. Histopathologically, the tumors in each group were similar to the subependymal giant cell astrocytoma that characterizes TSC.^23,24

Tuberous sclerosis complex is a heritable disorder characterized by a variety of hamartias and hamartomas, including congenital hypopigmented cutaneous macules (“ash-leaf sign”), facial angiofibromas (“adenoma sebaceum”), intracranial paraventricular or subependymal astrocytomas, cardiac rhabdomyoma, renal angiomyolipoma, and retinal astrocytic hamartomas. About 60% of cases are sporadic and 40% are familial that appear to be inherited in an autosomal dominant fashion.²⁵ However, the disorder is believed to be recessive at a molecular level, similar to retinoblastoma. About half of the cases with TSC show linkage to chromosome 9q34 and about half to chromosome 16p13.²⁶ The clinical manifestations of both types seems to be very similar.

Each of our patients had clinical findings compatible with TSC. The main ocular finding of TSC is the astrocytic hamartoma of the retina.^1-5 Less frequent ocular manifestations include patches of iris hypopigmentation and atypical inferior iris colobomas. Another recently described intraocular lesion in patients with TSC is hamartoma of the iris and ciliary body epithelium.⁶ This lesion usually is not appreciated clinically but has been found on histopathological examination of enucleation eyes. It was present in 2 of our patients and is possibly more common but overlooked clinically and histopathologically.

Retinal astrocytic hamartomas occur in about 50% of patients with TSC, about 50% of whom have bilateral retinal involvement.^4,5 This tumor can manifest as a small, sessile noncalcified lesion in the nerve fiber layer, as a multinodular yellow-white calcified lesion, or as a combination of the two.^4,5 Most are relatively small, ranging from 0.5 to 5.0 mm in diameter, and larger lesions are exceptional.

There have been a number of publications on retinal astrocytomas associated with TSC that remained fairly stable or, rarely, produced mild vitreous tumor seeding or vitreous hemorrhage but did not require enucleation. Those reports were not cited in this review, which only addressed lesions that were aggressive enough to require enucleation and undergo histopathologic studies.

It has been stressed that astrocytic hamartoma of TSC is generally a fairly stationary lesion that shows little or no tendency to grow.^3-5 The 4 cases reported here are clearly exceptions to that rule. Each showed slowly progressively enlargement that eventually caused total retinal detachment and neovascular glaucoma that required enucleation of the affected blind, painful eye.

The retinal tumors described in this report are similar to those that occur in the brain in patients with TSC. The characteristic brain lesion of TSC is the subependymal astrocytoma.^23,24 In both the brain and the retina, astrocytic hamartoma can be an isolated finding without other clinical evidence of TSC. Those in the brain, like those in the retina, are generally asymptomatic and are detected on radiographic evaluation. However, the subependymal astrocytoma of TSC sometimes can behave aggressively and cause a sudden increase in intracranial pressure, visual loss, and death.^23,24,27 However, the prognosis for life is good when they are surgically removed or decompressed.²⁷ It is of interest that such aggressive behavior in both the brain and retina is more likely to occur in very young children, often before age 5 years. In our review, the retinal astrocytic neoplasm appeared to require enucleation at a somewhat earlier age in children with TSC (mean, 9 years; Table 5) than those patients without TSC (mean, 20 years; Table 1).

The histopathology of retinal astrocytic hamartoma can vary from case to case. The typical small stationary astrocytic hamartoma typically is confined to the nerve fiber layer of the retina and is composed of elongated fibrous astrocytes with interlacing cytoplasmic processes.^1,2,28 The more aggressive tumors described in this report are comprised predominantly of large, plump cells with abundant eosinophilic cytoplasm, nuclear pleomorphism, and some mitotic activity. The tumors characteristically show extensive necrosis and calcospherites. These findings, found in our 4 cases, are virtually identical to those that characterize the subependymal giant cell astrocytoma of TSC.^22,23

Immunohistochemical analysis of the retinal giant cell astrocytoma characteristically shows a mixed glioneuronal phenotype. Despite the fact that the tumor has an overtly astrocytic appearance, the giant cells are often nonreactive or weakly positive for GFAP but typically stain strongly for NSE. Most tumors are also immunoreactive for S100 protein. This mixed immunophenotype suggests that the tumor is heterogeneous or hybrid in nature, expressing proteins of both glial and neuronal cells.²² Our cases tended to show a biphasic pattern of immunoreactivity; the larger giant cells were positive for NSE and negative or only weakly positive for GFAP, but the neighboring plump spindle cells were NSE and GFAP positive. These immunohistochemical properties are also similar to those of the giant cell astrocytomas of the central nervous system.^22,23

An intriguing aspect of our cases was that 3 patients had multiple, bilateral retinal astrocytomas, but only 1 of the tumors demonstrated progressive growth and complications. Each tumor that showed growth was located adjacent to the optic disc, and all 4 tumors invaded the optic nerve. It is of interest that neuropathologists still classify the giant cell astrocytoma of TSC as a benign neoplasm, despite the fact that it can slowly enlarge and demonstrate local invasion.^23,24 The more peripheral tumors in the ipsilateral and contralateral eyes remained stable and had no tendency to proliferate.

There have been several case reports of tumors that seem identical histopathologically to the cases reported here but occurred as unilateral solitary lesions in somewhat older patients who had no clinical findings of TSC.^7-17 We have chosen to call such lesions acquired retinal astrocytomas to differentiate them from the congenital astrocytic lesions that classically are associated with TSC.^1,2 However, it is not possible to categorically state that the acquired retinal astrocytoma is not a forme fruste of TSC in which the disease is expressed only as a solitary retinal lesion that may cause ocular complications somewhat later in life. It was not possible to perform genetic studies on our patients, but in the future genetic studies may answer the question as to whether the solitary acquired retinal astrocytoma is related to TSC.

The clinical differential diagnosis of the progressive retinal astrocytic hamartoma includes retinoblastoma, choroidal melanoma, and several other fundus conditions. In an infant or young child, systemic and ocular manifestations of TSC should suggest astrocytic hamartoma rather than retinoblastoma. Ophthalmoscopically, retinal astrocytic hamartoma characteristically shows an exudative retinal detachment with yellow, lipoproteinaceous exudation in the sensory retina and subretinal space. Such exudation is not seen in untreated retinoblastoma. Even though the retinal blood vessels that supply retinal astrocytic tumors are slightly dilated, they typically are not markedly dilated and tortuous as seen in a comparably sized retinoblastoma. In rare instances, a carefully planned fine- needle aspiration biopsy has been employed to differentiate retinal astrocytic hamartoma from retinoblastoma.²⁹ However that technique should be reserved for exceptional cases where the diagnosis has not been established by other methods.

In contrast to choroidal melanoma, progressive retinal astrocytic hamartoma is entirely amelanotic, produces yellow exudation, and is located in the sensory retina rather than the choroid.³⁰ In 1 reported case, the eye was enucleated with the diagnosis of melanoma.²¹ In retrospect, the typical fundus features and the finding of subependymal astrocytomas should have suggested the diagnosis of astrocytic hamartoma. A review of other reported cases that clinically simulated melanoma also shows features more suggestive of retinal astrocytoma.^9,10

Other fundus tumors like choroidal hemangioma, choroidal osteoma, and choroidal metastasis should not be confused with astrocytoma because they have distinguishing features and lack appreciable yellow retinal and subretinal exudation.³⁰ In addition, conditions that produce yellow exudation such as retinal capillary hemangioma and Coats disease have typical features that should differentiate them from retinal astrocytoma.^31,32

In summary, we reported 4 patients with TSC who developed progressive growth of a retinal astrocytic hamartoma, each of whom eventually required enucleation because of complications of neovascular glaucoma. The histopathologic features of these unusual tumors are identical to those seen with the subependymal giant cell astrocytoma of TSC. Similar lesions have been reported in patients without clinical manifestations of TSC and may represent a forme fruste of that syndrome. Progressive retinal astrocytic hamartoma has rather distinctive features that serve to differentiate it from retinoblastoma, choroidal melanoma, and other related fundus conditions.

Correspondence: Dr J. Shields, Ocular Oncology Service, Wills Eye Hospital, 840 Walnut St, Philadelphia, PA 19107 (jas.cls@comcast.net).

Financial Disclosure: None.

Funding/Support: This study was supported in part by the Eye Tumor Research Foundation, Philadelphia, Pa (Drs J. Shields and C. Shields); the Award of Merit in Retina Research, Houston, Tex (Dr J. Shields); the Macula Foundation, New York, NY (Dr C. Shields); and the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital, Philadelphia (Dr Eagle).

Previous Presentation: This article was presented as part of the first John Dickerson Lecture; May 3, 2003; Eastern Virginia Medical School, Norfolk, Va; at the annual meeting of the International Society of Genetic Eye Diseases; May 20, 2003; Paris, France; at the annual meeting of the American Society of Retinal Surgeons; August 20, 2003; New York, NY; and at the annual meeting of the American Ophthalmological Society; May 23-26, 2004; Hot Springs, Va, and subsequently published in Transactions of the American Ophthalmological Society (2004;102:139-148) and is published in the Archives of Ophthalmology after peer review and revision.

Acknowledgment: We thank Drs Stephen Sinclair, Abdel Hadj, Marwan Zeidan, David Doka, and Mark Wood for referral of the patients.

This article was corrected for error on November 24, 2015.